Background:  We have shown that histone deacetylase (HDAC), a host mediator of gene inhibition, can inhibit HIV gene expression and virus production, and contributes to quiescence of HIV within resting CD4⁺ T cells.  We tested the ability of valproic acid (VPA), an inhibitor of HDAC in wide clinical use, to induce expression of HIV from the resting CD4⁺ T cells of HIV-infected, aviremic patients.

Methods:  The capability of VPA to deacetylate the HIV promoter, a remodeling of chromatin linked to gene expression, was tested by chromatin immunoprecipitation.  The effect of VPA on resting CD4⁺ T cell phenotype was measured by flow cytometric analysis, and its effect on de novo HIV infection measured in ex vivo PBMC infections.  Resting CD4⁺ T cells were obtained by leukopheresis of 5 stably aviremic, HAART-treated HIV-infected donors, and outgrowth of HIV compared in limiting-dilution cultures after mitogen stimulation or exposure to VPA.  Infectious units per million resting cell estimates were made using the maximum likelihood method.

Results:  VPA induces acetylation at the integrated HIV proviral promoter, but CD4⁺ cells exposed to VPA do not become activated or more permissive for de novo HIV infection.  VPA induces outgrowth of HIV from the resting CD4⁺ cells of five of five aviremic patients at concentrations achievable in vivo with a frequently comparable to that of mitogen stimulation. 

Conclusions:  As further advances in the potency of antiretroviral therapy are made, HIV infection might be cleared by intensive but time-limited therapy, coupled with practical strategies that disrupt latency but do not enhance new infection.  HDAC inhibitors are capable of inducing expression of quiescent provirus without fully activating cells or enhancing de novo infection.  Although a relatively weak inhibitor, VPA may be useful in future clinical protocols that seek to eradicate HIV infection.

Keywords: latency; HDAC; valproic acid